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Biomedical subjects

L M DeCarli

Publications and source records attributed to L M DeCarli.

At least 19 recordsLinked to original sources
PubMed2001

Models of alcoholic liver disease in rodents: a critical evaluation.

This article represents the proceedings of a workshop at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were J. Christian Bode and Hiroshi Fukui. The presentations were (1) Essentials and the course of the pathological spectrum of alcoholic liver disease in humans, by P. de la M. Hall; (2) Lieber-DeCarli liquid diet for alcohol-induced liver injury in rats, by C. S. Lieber and L. M. DeCarli; (3) Tsukamoto-French model of alcoholic liver injury, by S. W. French; (4) Animal models to study endotoxin-ethanol interactions, by K. O. Lindros and H. Järveläinen; and (5) Jejunoileal bypass operation in rats-A model for alcohol-induced liver injury? by Christiane Bode, Alexandr Parlesak, and J. Christian Bode.

Animals↗
PubMed1998

Inducibility of cytochromes P-4502E1 and P-4501A1 in the rat pancreas.

Cytochrome P-450 (CYP) isoenzymes have been incriminated in the toxicity and carcinogenicity of various xenobiotics in different tissues, but prior measurements of their activity in pancreatic microsomes have been disappointing. We now applied new isolation methods and a highly sensitive procedure to assay for the metabolism of p-nitrophenol and 7-ethoxyresorufin, specific substrates for CYP2E1 (2E1) and CYP1A1 (1A1), respectively. 2E1 and 1A1 content was estimated with high-resolution chemiluminescent Western blots using recombinant 2E1 and 1A1 as standards. We found that p-nitrophenol hydroxylase activity was 5.07 +/- 0.66 and 1.50 +/- 0.26 pmol/ min/mg of protein in pancreatic microsomes of ethanol-fed and control rats, respectively. Chronic ethanol treatment increased 2E1 content in pancreatic microsomes 3.6-fold. Activity and content of 2E1 were also assessed in hepatic microsomes: specific activity (expressed per 2E1 content) was similar in pancreatic and hepatic microsomes. There was also an inductive effect of 3-methylcholanthrene (MC) on 1A1 in pancreatic microsomes. Pancreatic microsomal 7-ethoxyresorufin-O-dealkylation activity in MC-treated rats was 19.6 +/- 1.7 pmol/min/mg of protein, 61-fold higher than in controls. MC treatment increased the 1A1 content in pancreatic microsomes 42-fold. These results demonstrate that, in pancreatic microsomes, ethanol and MC exert striking inductive effects on 2E1 and 1A1 activities, which could play a role in the pathogenesis of pancreatitis and/or pancreatic cancer.

Animals↗
PubMed1997

Polyenylphosphatidylcholine decreases alcohol-induced oxidative stress in the baboon.

Diets supplemented with polyunsaturated fatty acids or triglycerides exacerbate alcohol-induced liver injury in rats, whereas, in baboons, polyenylphosphatidylcholine (PPC) protects against alcohol-induced fibrosis and cirrhosis. Because the aggravation in rats was attributed to enhanced lipid peroxidation, the present study was undertaken to assess parameters of oxidative stress in percutaneous liver biopsies of baboons fed alcohol, with or without PPC (2.8 g per 1000 calories). F2-isoprostanes and 4-hydroxynonenal, breakdown products of lipid peroxidation, were determined by gas chromatography/mass spectrometry, and alpha-tocopherol was measured by HPLC with electrochemical detection. Hepatic 4-hydroxynonenal was significantly increased in animals fed alcohol, but this was fully prevented by PPC. F2-isoprostanes were also significantly lower after PPC and ethanol than after ethanol alone, and the alcohol-induced glutathione decrease was attenuated. All of these parameters were normal in the animals withdrawn from alcohol, even with persistence of significant liver disease. Because peroxidation products are fibrogenic, their decrease could contribute to the antifibrogenic property of the phospholipids. In conclusion, PPC significantly attenuates ethanol-induced oxidative stress, which may explain, at least in part, its protective effect against alcoholic liver injury.

Alcoholism↗
PubMed1994

Phosphatidylcholine protects against fibrosis and cirrhosis in the baboon.

BACKGROUND/AIMS: Polyunsaturated soybean lecithin (55%-60% phosphatidylcholine [PC]) protects against fibrosis in alcohol-fed baboons. The present study was undertaken to determine whether PC is the active agent. METHODS: Virtually pure PC (equivalent to that contained in the lecithin) was administered for up to 6.5 years with or without alcohol, and the results were compared with those of unsupplemented groups. RESULTS: Control livers remained normal, whereas 10 of 12 baboons fed alcohol without PC developed septal fibrosis or cirrhosis with transformation of 81% +/- 3% of the hepatic lipocytes to collagen-producing transitional cells. By contrast, none of the eight animals fed alcohol with PC developed septal fibrosis or cirrhosis, and only 48% +/- 9% of their lipocytes were transformed, indicating that PC was indeed the protective compound. Ethanol feeding also resulted in decreased liver phospholipids and PC, and both were corrected by the supplementation. Furthermore, PC stimulated collagenase activity in cultured lipocytes. This PC consisted of several species, mainly dilinoleoylphosphatidylcholine (40%-52%) and palmitoyl-linoleoylphosphatidylcholine (23%-24%). Only dilinoleoylphosphatidylcholine duplicated the effect of the PC on collagenase. Other species of PC, phosphatidylethanolamine, free fatty acids, or choline were without effect. CONCLUSIONS: PC prevents alcohol-induced fibrosis and cirrhosis in nonhuman primates, and dilinoleoylphosphatidylcholine appears to be the active species, possibly by promoting collagen breakdown.

Animals↗
PubMed1990

S-adenosyl-L-methionine attenuates alcohol-induced liver injury in the baboon.

Chronic ethanol consumption by baboons (50% of energy from a liquid diet) for 18 to 36 mo resulted in significant depletion of hepatic S-adenosyl-L-methionine concentration: 74.6 +/- 2.4 nmol/gm vs. 108.9 +/- 8.2 nmol/gm liver in controls (p less than 0.005). The depletion was corrected with S-adenosyl-L-methionine (0.4 mg/kcal) administration (102.1 +/- 15.4 nmol/gm after S-adenosyl-L-methionine-ethanol, with 121.4 +/- 11.9 nmol/gm in controls). Ethanol also induced a depletion of glutathione (2.63 +/- 0.13 mumol/gm after ethanol vs. 4.87 +/- 0.36 mumol/gm in controls) that was attenuated by S-adenosyl-L-methionine (3.89 +/- 0.51 mumol/gm in S-adenosyl-L-methionine-methanol vs. 5.22 +/- 0.53 mumol/gm in S-adenosyl-L-methionine controls). There was a significant correlation between hepatic S-adenosyl-L-methionine and glutathione level (r = 0.497; p less than 0.01). After the baboons received ethanol, we observed the expected increase in circulating levels of the mitochondrial enzyme glutamic dehydrogenase: 95.1 +/- 21.4 IU/L vs. 13.4 +/- 1.8 IU/L; p less than 0.001, whereas in a corresponding group of animals given S-adenosyl-L-methionine with ethanol, the values were only 30.3 +/- 7.1 IU/L (vs. 9.6 +/- 0.7 IU/L in the S-adenosyl-L-methionine controls). This attenuation by S-adenosyl-L-methionine of the ethanol-induced increase in plasma glutamic dehydrogenase (p less than 0.005) was associated with a decrease in the number of giant mitochondria (assessed in percutaneous liver biopsy specimens), with a corresponding change in the activity of succinate dehydrogenase, a mitochondrial marker enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine Transaminase↗
PubMed1990

Attenuation of alcohol-induced hepatic fibrosis by polyunsaturated lecithin.

Characteristic features of alcoholic liver injury include fibrosis and striking membrane alterations, with associated phospholipid changes. To offset some of these abnormalities, a 10-yr study was conducted in baboons: 12 animals (eight females, four males) were fed a liquid diet supplemented with polyunsaturated lecithin (4.1 mg/kcal) for up to 8 yr, with either ethanol (50% of total energy) or isocaloric carbohydrate. They were compared with another group of 18 baboons fed an equivalent amount of the same diet (with or without ethanol), but devoid of lecithin. In the two groups, comparable increases in lipids developed in the ethanol-fed animals, but striking differences in the degree of fibrosis were seen. Whereas at least septal fibrosis (with cirrhosis in two) and transformation of their lipocytes into transitional cells developed in seven of the nine baboons fed the regular diet with ethanol, septal fibrosis did not develop in any animals fed lecithin (p less than 0.005). They did not progress beyond the stage of perivenular fibrosis (sometimes associated with pericellular and perisinusoidal fibrosis) and had a significantly lesser activation of lipocytes to transitional cells. Furthermore, when three of these animals were taken off lecithin, but continued on the same amount of the ethanol-containing diet, they rapidly (within 18 to 21 mo) progressed to cirrhosis, accompanied by an increased transformation of their lipocytes to transitional cells. These results indicate that some component of lecithin exerts a protective action against the fibrogenic effects of ethanol. Because we had previously found that choline, in amounts present in lecithin, has no comparable action, the polyunsaturated phospholipids themselves might be responsible for the protective effect.

Animals↗
PubMed1989

Experimental methods of ethanol administration.

Techniques are reviewed for the experimental feeding of alcohol, including a liquid diet procedure invented 25 years ago. This technique results in much higher ethanol intake than with other approaches. As a consequence, various complications observed in alcoholics can be reproduced in animal models. These include fatty liver, hyperlipemia, various metabolic and endocrine disorders, tolerance to ethanol and other drugs, physical dependence and withdrawal and, in the baboon, liver fibrosis and cirrhosis. Variations of the liquid diet formulation are compared, and adequacy of nutrition in terms of minerals, vitamins, lipotropes, carbohydrates and proteins is discussed. The importance of selecting proper controls is emphasized. The respective advantages of three standardized basic rat formulas are reviewed: (i) an all-purpose (35% fat) diet, comparable to the diet previously referred to as the "Lieber-DeCarli formula" and suitable for most experimental applications, particularly those intended to mimic the clinical situation in which the various effects of alcohol occur in the setting of hepatic changes characterized by a fatty liver; (ii) a low-fat diet comparable in all respects to the preceding diet but with a lower fat content, intended to minimize the hepatic changes, and (iii) a high-protein formula particularly useful in those circumstances in which an oversupply of dietary protein might be recommended (i.e. pregnancy). Variations of this technique, including continuous intragastric infusion, are also discussed. It is concluded that, for most experimental studies of chronic alcohol consumption, the liquid diet technique provides one of the most efficient tools to study the effects of ethanol under controlled nutritional conditions because it allows for alcohol consumption of clinical relevance and offers flexibility to adjust to special experimental or physiologic needs by allowing for various substitutions required for a particular experimental design, including changes in lipids, proteins or other dietary constituents. The technique also facilitates the comparison with controls by simplifying the pair feeding and is the best procedure available for the study of the toxic effects of alcohol and their interactions with deficiency or excess of various nutrients.

Administration, Inhalation↗
PubMed1989

Effects of mineral and vitamin supplementation on the alcohol-induced fatty liver and microsomal induction.

In rats fed ethanol (36% of total energy) for 1 month as part of a standard liquid diet, significant increases in hepatic lipids, microsomal cytochrome P-450, and in the activity of the microsomal ethanol oxidizing system were observed. Similar effects were noted in another group of animals treated with the same ethanol-containing diet, except that the content of minerals and vitamins was increased by 50%. Body weight gains were also comparable in these groups. It is concluded that these effects of ethanol are not due to vitamin and mineral deficiency secondary to decreased food intake but rather can be attributed to ethanol itself.

Alcohol Oxidoreductases↗
PubMed1989

Liquid diet technique of ethanol administration: 1989 update.

A technique of feeding alcohol as part of a liquid diet is reviewed that achieves an alcohol consumption of clinical relevance, while maintaining dietary control and providing adequate nutrition. With this procedure, blood alcohol levels are obtained which mimic clinical conditions and allow experimental duplications of many pathological complications caused by alcohol. In the rat, the liquid diet technique provides a model for the alcoholic fatty liver, various alcohol-induced metabolic, endocrine and central nervous system abnormalities (including tolerance and dependence) and the interaction of ethanol with industrial solvents, many commonly used drugs, analgesics, carcinogens and nutrients. This technique also resulted in the discovery of a new pathway of ethanol metabolism in the microsomes involving an ethanol-specific cytochrome P-450 (P450IIE1), which has now been confirmed in man. P450IIE1 contributes not only to the metabolic tolerance to ethanol, but also explains the enhanced susceptibility of the alcoholic to many ubiquitous xenobiotic agents. The liquid diet technique provides the flexibility to adjust to special experimental or physiological needs by allowing for various substitutions including changes in lipids, proteins or other dietary constituents. This procedure is thereby ideally suited for the study of the interactions of alcohol with deficiency or excess of various nutrients. The technique also facilitates the comparison with controls by simplifying pair feeding procedures. Although the flexibility of the liquid diet technique is one of its key advantages, a standard 'all purpose' liquid diet is described which is appropriate for most experimental applications. In addition, two other general formulae are given, namely a low fat diet (that allows the study of the effects of ethanol in the presence of minimal hepatic lipid accumulation) and a high protein diet (to meet increased needs, e.g. during pregnancy and lactation). The optimal amount of ethanol for the rat liquid diet was found to be 5 g/dl or 36% of total energy. With lesser amounts of alcohol, intake falls below a critical threshold; blood levels of alcohol then become negligible and the model becomes irrelevant to clinical conditions. In the rat, amounts of ethanol above 5 g/dl were not found to be associated with any further gain in alcohol ingestion. By contrast, in the baboon, the ethanol content could be raised profitably to 7 g/dl or 50% of total energy and resulted in the development of cirrhosis. This higher alcohol intake, together with species difference, may explain the greater severity of liver lesions produced by alcohol in the baboon.(ABSTRACT TRUNCATED AT 400 WORDS)

Alcohol Drinking↗
PubMed1988

Role of acetone, dietary fat and total energy intake in induction of hepatic microsomal ethanol oxidizing system.

Chronic ethanol consumption results in the induction of a specific hepatic cytochrome P-450 (P450IIE1). However, since compounds other than ethanol (i.e., acetone) can also serve as P450IIE1 inducers, and since ethanol given with a normal fat-containing (35% of energy) diet is associated with acetonemia, hepatic steatosis and decreased body weight gain, the question has been raised whether induction is mediated specifically by ethanol or whether it might represent a nonspecific response to these other factors. This was investigated by varying both the mode of ethanol administration and the composition of the diet. By administering ethanol in the drinking water, or as part of a low-fat (5% of energy) liquid diet, a significant induction of P450IIE1 and of the activities of the microsomal ethanol oxidizing system and p-nitrophenol hydroxylase was demonstrated in the absence of any significant increase in blood acetone with minimal increase in liver total lipids. Induction of P450IIE1 was comparable with the low or normal fat-containing diets, but MEOS activity rose more with the latter, possibly reflecting a potentiating effect of dietary fat on ethanol oxidation by P-450 enzymes other than P450IIE1. When the lack of weight gain of the alcohol fed animals was mimicked in controls by decreasing the amount of diet ingested, no induction was observed. Varying the pattern of liquid diet feeding had no demonstrable differential effect. Thus, the induction of P450IIE1 after chronic ethanol consumption can be attributed to ethanol itself, but dietary fat can potentiate the induction of the microsomal ethanol oxidizing system and of p-nitrophenol hydroxylase.

Acetone↗
PubMed1982

The feeding of alcohol in liquid diets: two decades of applications and 1982 update.

The technique of feeding ethanol as part of a totally liquid diet was invented two decades ago and its successful application for the intervening period is reviewed. This technique results in much higher ethanol intake than with conventional procedures. As a consequence, various complications observed in alcoholics were reproduced in animal models, including fatty liver, hyperlipemia, various metabolic and endocrine disorders, tolerance to ethanol and other drugs, physical dependence and withdrawal, the fetal alcohol syndrome and, in the baboon, liver fibrosis and cirrhosis. Variations of the liquid diet formulation are compared and three standardized basic formulas are being proposed for the rat: (1) a regular diet, comparable to the diet previously referred to as the "Lieber-DeCarli Formula" and suitable for most experimental applications, particularly those intended to mimic the clinical situation in which the various effects of alcohol occur in the setting of liver changes characterized by a fatty liver; (2) a low fat diet comparable in all respects to the preceding diet but with a lower fat content, intended to minimize the hepatic changes; and (3) a high protein formula particularly useful in those circumstances in which an oversupply of dietary protein might be recommended (i.e., pregnancy and lactation).

Alcoholism↗
PubMed1975

Effect of chronic alcohol consumption on ethanol and acetaldehyde metabolism.

Hepatic metabolism of ethanol to acetaldehyde by the alcohol dehydrogenase (ADH) pathway is associated with the generation of reducing equivalents as NADH. Conversely, reducing equivalents are consumed when ethanol oxidation is catalyzed by the NADPH dependent microsomal ethanol oxidizing system (MEOS). Since the major fraction of ethanol metabolism proceeds via ADH and since the oxidation of acetaldehyde also generates NADH, an excess of reducing equivalents is produced. This explains a variety of effects following acute ethanol administration, including hyperlactacidemia, hyperuricemia, enhanced lipogenesis and depressed lipid oxidation. To the extent that ethanol is oxidized by the alternate MEOS pathway, it slows the metabolism of other microsomal substrates. Following chronic ethanol consumption, adaptive microsomal changes prevail, which include enhanced ethanol and drug metabolism, and increased lipoprotein production. Eventually, injury develops with alterations of the rough endoplasmic reticulum and structural and functional abnormalities of the mitochondria.

Acetaldehyde↗